The compounds of the vitamin D series are well known as agents essential for controlling calcium homeostasis in the animal or human. It is also known that it is not vitamin D itself, but metabolites generated from it in the animal or human body, that are effective in regulating calcium metabolism. In this context, the most important vitamin D metabolite is 1.alpha.,25-dihydroxyvitamin D.sub.3 (1,25-(OH).sub.2 D.sub.3). This compound, as well as certain structural analogs, such as 1.alpha.-hydroxyvitamin D.sub.3 (1.alpha.-OH-D.sub.3), 1.alpha.-hydroxyvitamin D.sub.2 (1.alpha.-OH-D.sub.2), or certain fluorine substituted 1,25-(OH).sub.2 D.sub.3 derivatives, are highly potent in stimulating intestinal calcium absorption, as well as the resorption of calcium from bone (bone mobilization). As a consequence, these compounds are now used, or have been proposed for use, as pharmaceutical agents for the treatment of a variety of calcium metabolism disorders, such as renal osteodystrophy, hypoparathyroidism, vitamin D-resistant rickets, or osteoporosis.
More recent research has established that 1,25-(OH).sub.2 D.sub.3, in addition to its role in regulating calcium homeostasis in vivo, also expresses other biological functions. Specifically, it has been shown that 1,25-(OH).sub.2 D.sub.3, and compounds closely related to it (e.g. 1.alpha.-OH-D.sub.3, or fluoro analogs of 1,25-(OH).sub.2 D.sub.3) are highly potent in inducing cell differentiation. Most importantly, it has been found that 1,25-(OH).sub.2 D.sub.3 will inhibit the proliferation of malignant cells (specifically, leukemia cells) and bring about their differentiation, in culture, to normal monocytes [Abe, et al., Proc. Natl. Acad. Sci. U.S.A. 78, 4990 (1981); Honma et al., ibid, 80, 201 (1983)]. Because of this remarkable activity, 1,25-(OH).sub.2 D.sub.3 and related compounds have been proposed as anticancer, specifically antileukemic, agents (Suda et al., U.S. Pat. No. 4,391,802). However, even though these compounds are, indeed, highly effective in differentiating malignant cells in culture, their practical use in differentiation therapy as anticancer agents is severely limited because of their equally high potency as agents affecting calcium metabolism. At the levels required in vivo for effective use as antileukemic agents, these same compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. This calcemic activity precludes, or severely limits, the use of these known vitamin D compounds in the treatment of malignancies, and indicates a need for compounds with greater specificity and selectivity of action.
In this disclosure the terms `calcemic activity` or `calcemic action` are intended as a short-hand designation of the well-known ability of vitamin D compounds to raise blood calcium levels by virtue of their stimulation of intestinal calcium absorption (Ca transport) and of calcium resorption from bone (bone mobilization). The term `differentiation activity` refers to the more recently discovered activity of certain vitamin D compounds in arresting the proliferation of malignant cells and inducing their differentiation to normal cells.
Previous work has led to the preparation of several compounds with enhanced differentiation activity. Thus, U.S. Pat. No. 4,717,721, as well as other publications [Ostrem & DeLuca, Steroids, 49 73-102 (1988); Ostrem et al., J. Biol. Chem. 262, 14164 (1987)] disclose that 1,25-(OH).sub.2 D analogs in which the side chain is elongated by one carbon, exhibit a differentiation activity for leukemia cells about ten times greater than 1,25-(OH).sub.2 D.sub.3 itself. However, such compounds still are approximately as potent as 1,25-(OH).sub.2 D.sub.3 in stimulating calcium absorption and elevating serum calcium levels, and thus do not overcome the problem of the undesired potent `calcemic action` discussed above. Thus, although such compounds show an improved differentiation/calcemic activity ratio, they are not selective in that their calcemic potency is as high as that of the parent compound (1,25-(OH).sub.2 D.sub.3). Other vitamin D-related compounds, which are said to exhibit preferential differentiation activity, have been reported [Ostrem et al., supra; Kubodera et al. Chem. Pharm. Bull. 34, 2286-89 (1986); Ikekawa et al. Chem. Pharm. Bull. 35, 4362 (1987)], but these are structurally distinct and different from the compounds of the present invention.